Macrophage colony-stimulating factor and receptor activator NF-κB ligand fail to rescue osteoclast-poor human malignant infantile osteopetrosis in vitro

Malignant infantile osteopetrosis (MIOP) is a disease characterized by failure in bone resorption, leading to dense fragile bones with a severely reduced bone marrow cavity. Normal or increased numbers of osteoclasts are present in the common variant of this disease; in such cases, the defect is likely to be inherent to the mature osteoclast and can be cured by bone marrow transplantation. However, MIOP also results from failure of osteoclast formation (osteoclast-poor MIOP). We report on two infants diagnosed with osteoclast-poor MIOP and utilize modern cell culture techniques to investigate the pathogenesis of disease. Peripheral blood mononuclear cells (PBMNCs) from these children were cultured in the presence of recombinant macrophage colony-stimulating factor and receptor activator NF-(K)B ligand for up to 3 weeks. Control cultures included PBMNCs from age-matched children, one of whom had an osteoclast-rich form of MIOP. Formation of osteoclasts (cells coexpressing vitronectin receptor and F-actin rings) occurred in all the control cultures. Significant bone resorption occurred in cultures from PBMNCs of the healthy individuals, whereas almost no bone resorption occurred in the osteoclast-rich MIOP cultures. In contrast, PBMNC cultures from the osteoclast-poor MIOP child formed only very occasional small F-actin ring-positive osteoclasts, which coexpressed vitronectin receptor and cathepsin K, and extremely rare foci of resorption. Because neither macrophage colony-stimulating factor nor receptor activator NF-(K)B ligand rescued the defect in osteoclast differentiation in the two cases of osteoclast-poor MIOP in vitro, there would be little benefit in treating these children with either of these recombinant proteins. Finally, these results demonstrate that this experimental culture model replicates the human osteopetrosis phenotype observed in vivo and should prove useful in analyzing the pathogenesis of the various forms of MIOP. (C) 2002 by Elsevier Science Inc. All rights reserved.